Cavernous Smooth Muscle Research Articles

Tadalafil Increases Akt and Extracellular Signal-Regulated Kinase 1/2 Activation, and Prevents Apoptotic Cell Death in the Penis Following Denervation

Despite techniques to preserve the cavernous nerves during radical prostatectomy erectile dysfunction remains a complication. We determined whether bilateral cavernous nerve resection induces apoptosis in the penis. We also determined whether treatment with the phosphodiesterase-5 inhibitor tadalafil prevents apoptosis as well as the specific mechanisms involved. Mice were subjected to cavernous nerve resection or sham surgery. Penises were processed for the identification of apoptotic cells, changes in phosphorylation of several protein kinases and immunolocalization of specific kinases. Mice were also placed on tadalafil or vehicle after cavernous nerve resection and the penises were processed as described. Statistical analysis was performed with the Mann-Whitney U test for comparisons among groups or Student's t test. An increase in apoptotic cavernous smooth muscle and endothelial cells was evident by 2 weeks, which further increased 4 and 6 weeks after cavernous nerve resection. Apoptosis coincided with an increase in the phosphorylation of c-jun N-terminal kinase and p38 mitogen activated protein kinase. Phospho-c-jun N-terminal kinase was immunolocalized to endothelial and smooth muscle cells. Treatment with tadalafil decreased the number of apoptotic cells and increased the phosphorylation of the 2 survival associated kinases Akt and extracellular signal-regulated kinase 1/2. These results provide a rationale for the early use of phosphodiesterase-5 inhibition following radical prostatectomy or extensive pelvic surgery, during which there may be injury to the cavernous nerves, to aid in the return of erectile function.

Alterations of NOS, arginase, and DDAH protein expression in rabbit cavernous tissue after administration of cigarette smoke extract

Cigarette smoking is an independent risk factor for vasculogenic erectile dysfunction (ED). Nitric oxide (NO) has been demonstrated to be the principal mediator of cavernous smooth muscle relaxation and penile erection. Therefore, we examined whether or not enzyme activities and factors involved in the NO generation pathway are affected in rabbit corpus cavernosum after administration of nicotine- and tar-free cigarette smoke extract (CSE). CSE was prepared by bubbling a stream of cigarette smoke into phosphate-buffered saline. CSE was injected subcutaneously into adult male rabbits once a day for 5 wk. In the CSE group, significantly decreased cyclic GMP production as a marker of NO generation was associated with attenuated overall nitric oxide synthase (NOS) activity, enhanced arginase activity, accumulation of endogenous NOS inhibitors such as monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA), and decreased dimethylarginine dimethylaminohydrolase (DDAH) activity as an metabolizing enzyme of endogenous NOS inhibitors. Neuronal NOS (nNOS) and DDAH I protein expression were decreased without altering endothelial NOS expression, while arginase I expression was upregulated. These results suggest that impaired NO production would result from blunted NOS activity, which is possibly brought about by the downregulation of nNOS protein, accumulation of endogenous NOS inhibitors, and enhanced arginase activity together with upregulation of arginase I protein in cavernous tissue. The impaired DDAH activity due to decreased expression of DDAH I protein would result in an accumulation of endogenous NOS inhibitors with CSE. These alterations may be relevant to induction of the erectile dysfunction following CSE.

On the pathogenesis of penile venous leakage: role of the tunica albuginea

BackgroundEtiology of venogenic erectile dysfunction is not exactly known. Various pathologic processes were accused but none proved entirely satisfactory. These include presence of large venous channels draining corpora cavernosa, Peyronie's disease, diabetes and structural alterations in fibroblastic components of trabeculae and cavernous smooth muscles. We investigated hypothesis that tunica albuginea atrophy with a resulting subluxation and redundancy effects venous leakage during erection.Methods18 patients (mean age 33.6 ± 2.8 SD years) with venogenic erectile dysfunction and 17 volunteers for control (mean age 31.7 ± 2.2 SD years) were studied. Intracorporal pressure was recorded in all subjects; tunica albuginea biopsies were taken from 18 patients and 9 controls and stained with hematoxylin and eosin and Masson's trichrome stains.ResultsIn flaccid phase intracorporal pressure recorded a mean of 11.8 ± 0.8 cm H2O for control subjects and for patients of 5.2 ± 0.6 cm, while during induced erection recorded 98.4 ± 6.2 and 5.9 ± 0.7 cmH2O, respectively. Microscopically, tunica albuginea of controls consisted of circularly-oriented collagen impregnated with elastic fibers. Tunica albuginea of patients showed degenerative and atrophic changes of collagen fibers; elastic fibers were scarce or absent.ConclusionStudy has shown that during erection intracorporal pressure of patients with venogenic erectile dysfunction was significantly lower than that of controls. Tunica albuginea collagen fibers exhibited degenerative and atrophic changes which presumably lead to tunica albuginea subluxation and floppiness. These tunica albuginea changes seem to explain cause of lowered intracorporal pressure which apparently results from loss of tunica albuginea veno-occlusive mechanism. Causes of tunica albuginea atrophic changes and subluxation need to be studied.

Functional and Morphological Improvement in Erectile Tissue of Hypertensive Rats by Long-Term Combined Therapy with Phosphodiesterase Type 5 Inhibitor and Losartan

Erectile dysfunction (ED) is highly associated to cardiovascular disease, especially arterial hypertension. Phosphodiesterase type 5 (PDE5) inhibitors and angiotensin II receptor blockers (ARB) are both common and efficient therapy in patients with ED and arterial hypertension, respectively. To evaluate the effect of PDE5 inhibitor, sildenafil (S), and of ARB Losartan (L) in a continuous combined therapy for a long term on penile structures in a hypertensive rat model. During 6 months, four groups of male spontaneously hypertensive rats (SHR) and one of Wistar-Kyoto (WKY) rats, as control group, were studied: no-treatment SHR, SHR with L, SHR with S, SHR with S + L, and no-treatment WKY. Cavernous smooth muscle (CSM) and vascular smooth muscle (VSM) from cavernous arteries, collagen type III (COL-III), and endothelial nitric oxide synthase (eNOS) expression in cavernous space were evaluated. Functional and morphological differences between S and L in a continuous combined therapy vs. either drug as monotherapy on penile structures. After 6 months, SHR that received L, S, or combined therapy showed a similar reduction in blood pressure compared with untreated SHR. Nevertheless, SHR + L + S and control WKY showed significantly lower values of (i) CSM (P < 0.01), (ii) VSM (P < 0.01), and (iii) COL-III (P < 0.01) when compared with the untreated SHR and also with the SHR with monotherapy. Additionally, SHR + L + S, presented a higher eNOS expression in sinusoidal endothelium in comparison with the untreated SHR and the SHR with monotherapy (P < 0.01). In vitro studies revealed that SHR + L + S displayed a better relaxation response to acetylcholine than the untreated SHR and the SHR with monotherapy (P < 0.01). These results suggest that a long-term combined therapy using L and S is a useful tool for functional and structural modification in cavernous tissue from SHR.

Hydrogen Sulphide: A Novel Endogenous Gasotransmitter Facilitates Erectile Function

In a pilot study, we found that the novel gasotransmitter, hydrogen sulfide (H2S), had a vasodilatory and proerectile action on the cavernosum. In the present work, we explored the ability of the cavernosum to synthesize H2S and its mechanism on the cavernosal pathways. To evaluate the physiopharmacological responses and mechanism in the erectile function of H2S in rabbit cavernosum. Rabbit corpus cavernosum (CC) smooth muscle tissue (N = 5) was homogenized and incubated with L-cysteine (10 mM) and pyridoxal 5'-phosphate (2 mM) to detect H2S formation. In isometric tension studies on rabbits (N = 12), the effect of sodium hydrogen sulfide (NaHS; stable H2S donor, 100 microM-3.2 mM) was evaluated on the relaxant and contractile pathways in the cavernous smooth muscle using standard pharmacological tools. In vitro evidences for cavernosal H2S formation and proerectile pharmacological effects. H2S was readily synthesized in the rabbit CC (2.1 +/- 0.4 nmol/mg protein). In organ bath studies, NaHS consistently relaxed the rabbit CC in a concentration-dependent manner. MDL 12,330A and 1-H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one inhibited the NaHS relaxation by 22.5% and 14.7%, respectively. All three enzyme inhibitors (aminooxyacetic acid [AOAA], beta-cyanoalanine [beta-CA], and DL-propargylglycine [PAG][1 mM]) markedly increased the noradrenergic contractile neurotransmission of CC strips to field stimulation with minimal reversal by cysteine (1 mM) indicating the possible inherent inhibition of the relaxant H2S formation. AOAA, beta-CA, or PAG had no significant effect on nitrergic relaxation of noradrenaline-precontracted CC strips. These pioneering studies provide evidence for the endogenous formation of H2S and its proerectile relaxant effect on the cavernosum, with the possibility of involvement of the cyclic adenosine monophosphate pathway.

Relaxation degree of cavernous smooth muscle: a novel parameter to predict postoperative success in penile revascularization

To investigate the role of a new preoperative parameter, relaxation degree (RD), in the prediction of postoperative success after deep dorsal vein arterialization operations. Chart reviews and electromyographic recordings were evaluated in 52 patients on whom deep dorsal vein arterialization was carried out for pure caverno-occlusive dysfunction. The efficiacy of the operation was assessed as improvement or failure according to the five-item version of international index of erectile function (IIEF). RD was defined as the percentage decrease in cavernous electrical activity (CEA) after intracavernous papaverine injection. Preoperative RD measurements were statistically compared between the improvement and the failure groups. The mean age of patients was 34.2 +/- 8.1 years (range 25-49) with a mean follow-up of 32 +/- 8 months. Improvement was observed in 39 (75%) and failure in 13 (25%) patients. The mean RD values were 60% and 32% for surgical improvement and failure groups respectively (P < 0.01). In patients with mild ED, the mean RD value was 70.3% whereas it was 28.7% in patients with severe ED. The RD value of greater than 40% predicts surgical success with a specifity of 75% and a sensitivity of 90%. The RD value of cavernous muscle seems to decrease as the severity of ED increases. In addition, RD may predict the outcome of penile revascularization operations and it may be a useful preoperative indicator for surgical success.

Potential differentiation of human mesenchymal stem cell transplanted in rat corpus cavernosum toward endothelial or smooth muscle cells

One of the causes of erectile dysfunction (ED) is the damaged penile cavernous smooth muscle cells (SMCs) and sinus endothelial cells (ECs). To investigate the feasibility of applying immortalized human mesenchymal stem cells (MSCs) to penile cavernous ECs or SMCs repair in the treatment of ED, the in vivo potential differentiation of the immortalized human MSCs toward penile cavernous endothelial or smooth muscle was investigated. One clone of immortalized human bone marrow mesenchymal stem cell line B10 cells via retroviral vector encoding v-myc were transplanted into the cavernosum of the Sprague-Dawley rats and harvested 2 weeks later. The expression of CD31, von Willebrand factor (vWF), smooth muscle cell actin (SMA), calponin and desmin was determined immunohistochemically in rat penile cavernosum. Multipotency of B10 to adipogenic, osteogenic or chondrogenic differentiation was found. Expression of EC specific markers (CD31 or vWF protein) and expression of SMC specific markers (calponin, SMA or desmin protein) were demonstrated in grafted B10 cells. When human MSCs were transplanted into the penile cavernosum, they have the potential to differentiate toward ECs or SMCs. Human MSCs may be a good candidate in the treatment of penile cavernosum injury.

P643 Causes of liver related death in HIV-infected patients in France: mortality 2005 Survey

Recently, growing clinical evidence has suggested that sexual dysfunction is more prevalent in women with overactive bladder (OAB).However, there has been no basic research to clarify the relationship between OAB and female sexual dysfunction. Therefore, we investigated this issue using a rabbit model of OAB.Twenty-seven New Zealand white female rabbits were randomly divided into the OAB and control groups.The contractile responses of clitoral cavernous strips to K+, phenylephrine (PE), Bay K 8644, and endothelin (ET)-1, and the relaxation responses of acetylcholine (ACh), sodium nitroprusside (SNP), and Y-27632 to PE-induced contraction by measuring isometric tension.The contractile responses to K+, PE, Bay K 8644, and ET-1 were significantly more increased in the OAB group in a dose-dependant manner than in the control group (P < 0.05), and the responses to ET-1 were more prominent than those to the remaining substances (P < 0.01). The increased contractile responses to ET-1 were blocked by BQ123 (ETA receptor antagonist) but not by BQ788 (ETB receptor antagonist). Clitoral cavernosal strips from the OAB group were more difficult to relax than those from the control group in terms of ACh- and SNP-induced relaxation (P < 0.05). The Y-27632-induced relaxant responses to PE- and ET-1-induced contraction were less prominent in the OAB group than in the control group.The results of this study provide evidence that female OAB may deteriorate clitoral engorgement, which is associated with a greater force generation by increased calcium sensitization and subsequently decreased of relaxation. The activation of ET and Rho-kinase system may be crucial to negatively effect the clitoral smooth muscle relaxation in experimentally induced OAB animal model. But whether these vasomotor effects are revived in human clitoris is still debatable. Myung S-C, Lee M-Y, Lee S-Y, Yum S-H, Park S-H, and Kim S-C. Contractile changes of the clitoral cavernous smooth muscle in female rabbits with experimentally induced overactive bladder.

Corpus Cavernosum Electromyography with Revised Methodology: An Explorative Study in Patients with Erectile Dysfunction and Men with Reported Normal Erectile Function

A lack of standardization of the recording techniques of corpus cavernosum electromyography (CC-EMG) and objective criteria to characterize the recorded signals (CC-potentials) are the main difficulties hindering the clinical application of this method. These difficulties have been recently overcome by revising the recording and interpretation methodology of CC-EMG AIM: To assess if CC-EMG performed with the revised methodology is discriminative for well-defined clinical conditions in patients with erectile dysfunction (ED). Based on blinded clinical diagnosis, ED patients were catalogued into five subgroups: severe penile fibrosis, cavernous arterial insufficiency (CAI), cardio-vascular comorbidity (CVCM) without proven CAI, post-radical retropubic prostatectomy (RRP), and psychogenic ED. With four electrodes placed on the penile shaft bilaterally, CC-EMG was recorded monopolarly for 30 minutes during flaccidity. After evaluation of the recordings by visual inspection, CC-potentials were analyzed using cross- and autocorrelation techniques. The parameters evaluated were amplitude, duration, dominant frequency (DF), and maximum cross-correlation coefficient (Rmax) of CC-potentials recorded from proximal and distal parts of the CC. Comparison of the values of parameters amplitude, duration, DF, and Rmax between patient and control groups. A total of 119 patients with ED and 43 men with reported normal erectile function were studied. Thirteen out of 14 patients with severe penile fibrosis did not show any distinguishable CC-potential. Patients with CAI had significantly decreased amplitude compared with the potent controls, as well as the patients with CVCM but without proven CAI. Significantly decreased amplitude and Rmax were detected in ED patients following RRP compared with the controls. Corpus cavernosum electromyography performed with the revised methodology is able to discriminate ED patients with conditions that are associated with cavernous smooth muscle degeneration and/or autonomic neuropathy from men with reported normal erectile function.

In Vivo and in Vitro Effects of Nebivolol on Penile Structures in Hypertensive Rats

Erectile dysfunction is associated with high blood pressure and antihypertensive treatment, especially diuretics and traditional beta-blockers. Nevertheless, new beta-blockers such as nebivolol present some differences with respect to the classic beta-blockers. The aim of this study was to determine the functional and morphologic effects of nebivolol on penile structures in hypertensive rats. During a 6-month period, male spontaneously hypertensive rat (SHR) and Wistar-Kyoto (WKY) rats were studied. The groups were as follows: 1) untreated SHR (Untreated-SHR); 2) SHR given nebivolol 10 mg/kg/day (SHR+N); 3) SHR given amlodipine 3 mg/kg/day (SHR+AML); and 4) untreated WKY (untreated-WKY). Cavernous smooth muscle (CSM) and vascular smooth muscle (VSM) from cavernous arteries, as well as collagen type III (COL III) in cavernous tissue, were evaluated. After 6 months, SHR groups given nebivolol and amlodipine showed similar reductions in blood pressure compared with untreated SHR. However, only SHR+N and control WKY showed significantly lower values of CSM (P < 01), VSM (P < 01), and COL III (P < 01) when compared with untreated SHR and SHR+AML. In addition SHR+N showed a higher endothelial nitric oxide synthase expression in sinusoidal endothelium compared with SHR, and SHR+AML (P < 01). In vitro studies revealed that SHR+N displayed a better relaxation response to acetylcholine than untreated-SHR and SHR+AML (P < 01). Nebivolol presented equivalent BP control compared with amlodipine. However, only nebivolol showed a significant better functional outcome with a protective role against structural changes in erectile tissue that are caused by arterial hypertension.

Effects of icariin on phosphodiesterase-5 activity in vitro and cyclic guanosine monophosphate level in cavernous smooth muscle cells

Objectives To investigate the effect of icariin on the cyclic guanosine monophosphate (cGMP)-hydrolytic activity of phosphodiesterase-5 (PDE5) isoforms and the cGMP levels in cavernous smooth muscle cells treated with sodium nitroprusside (SNP). Methods PDE5 isoforms (PDE5A1, A2, and A3) were isolated from sf9 insect cells infected with baculoviruses carrying PDE5 isoform cDNA. Icariin was isolated from Epimedii herba. Varying amounts (10 −6 to 10 −11 M) of icariin or zaprinast were added to reaction mixtures containing PDE5 isoforms and cGMP. The inhibitory effects of icariin and zaprinast were analyzed by GraphPad Software and are expressed as concentration that inhibits 50% (IC 50) values. Cavernous smooth muscle cells were isolated from 3-month-old rats, treated with icariin (100 and 200 μM) or zaprinast (200 μM) for 15 minutes, and then with 10 μM SNP for 30, 60, 120, 240, and 360 minutes. The cells were then analyzed for the cGMP concentration using an enzyme immunoassay system. Results Icariin inhibited PDE5A1, A2, and A3 with an IC 50 value of 1.0, 0.75, and 1.1 μM, respectively. The corresponding IC 50 values for zaprinast were 0.33, 0.23, and 0.32 μM. Icariin consistently outperformed the control (SNP-only treatment) in maintaining greater cGMP levels, particularly at the greater concentration of 200 μM. In contrast, zaprinast at 200 μM did better than the control only at 60 and 360 minutes. Conclusions Icariin was inhibitory to all three PDE5 isoforms with similar IC 50 values, which were approximately three times greater than those for zaprinast. Icariin was able to enhance cGMP levels in SNP-treated cavernous smooth muscle cells.

Effects of l-norgestrel on the endothelium-dependent relaxation response of rabbit clitoral cavernous smooth muscles

To determine the effect of a popular oral contraceptive, L-norgestrel (a synthetic progestogen), on relaxing response of clitoral cavernous smooth muscles. Prospective, randomized study. Academic facility. Thirty adult female New Zealand White rabbits. We conducted isometric tension studies with norepinephrine, endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside) vasodilators, and L-norgestrel. The effects of nonspecific nitric oxide synthase inhibitor (N(w)-nitro-L-arginine methyl ester) and the potassium channel blockers (1 and 10 mM tetraethylammonium as well as 10 microM glibenclamide) on the reactivities of clitoral cavernous strips were investigated. Causation and power of developed tension after treatment. Acetylcholine, sodium nitroprusside, and L-norgestrel produced concentration-dependent relaxation of the norepinephrine-precontracted strips. Both endothelium removal and treatment with 10 microM N(w)-nitro-L-arginine methyl ester completely inhibited the relaxation response to acetylcholine and L-norgestrel, and supplementation with 10 mM L-arginine partially reversed the inhibition. Incubation with either tetraethylammonium (TEA) or glibenclamide reduced the L-norgestrel-induced relaxation in a dose-independent manner. The L-norgestrel-induced relaxation of the clitoral cavernous smooth muscle is endothelium and nitric oxide dependent and may be related to more than two types of potassium channels activation.

Differences Between Candesartan and Hydralazine in the Protection of Penile Structures in Spontaneously Hypertensive Rats

Previous studies indicate that angiotensin type I receptor antagonists present a beneficial effect on penile structures in hypertensive rats. However, at present there is no substantial information concerning the functional aspect of this class of antihypertensive drugs. To determine, by in vitro studies, functional effects of Candesartan in comparison with a traditional vasodilating agent, Hydralazine, on penile structures in a rat model of arterial hypertension. During 4 months, three groups of male spontaneously hypertensive rats (SHR) and one of Wistar-Kyoto (WKY) rats, as control group, were studied: SHR without treatment; SHR with Candesartan cilexetil 7.5 mg/kg/day; SHR with Hydralazine 50 mg/kg/day; and WKY rats without treatment. Cavernous smooth muscle strips were mounted in an organ bath system for in vitro studies. In addition, cavernous smooth muscle and vascular smooth muscle from cavernous arteries, cavernous tissue fibrosis, and collagen type III were also evaluated by immunohistochemistry. After 4 months, SHR with Candesartan and Hydralazine showed similar reduction in blood pressure compared with untreated SHR. However, in vitro studies revealed that SHR with Candesartan displayed a better relaxation response to acetylcholine than SHR and SHR with Hydralazine (P < 0.01). Immunostaining indicates that only SHR with Candesartan and control WKY rats showed significantly lower values of: (i) cavernous smooth muscle (P < 0.01); (ii) vascular smooth muscle (P < 0.01); and (iii) collagen type III (P < 0.01) when compared with untreated SHR or SHR with Hydralazine. Additionally, SHR with Candesartan presented a higher endothelial nitric oxide synthase expression in sinusoidal endothelium in comparison with SHR, and SHR with Hydralazine (P < 0.01). Candesartan presented equivalent blood pressure control compared with Hydralazine. However, only Candesartan showed a significant better response to acetylcholine, in in vitro studies, with a protective role against structural changes in vessels as well as in cavernous spaces of the erectile tissue.

Butea superba Roxb. enhances Penile erection in rats

This study aimed to investigate the effects of ethanol extracts of Butea superba in increasing intracavernous pressure (ICP) in vivo. The extracts were prepared from fresh and dried root cores and fresh and dried root barks. Penile erection was induced in aged rats by electrical stimulation of the cavernous nerve. Cavernous smooth muscle relaxation was also observed in vitro in the presence of the extract, cGMP or isobutyl-methylxanthine (IBMX) alone or the extract together with cGMP or IBMX. The dried root core extract from Phrae was the most effective in increasing the ICP. The dose-response relationship study revealed a bell-shape curve with the maximum effective dose at 1 mg/kg. The ICP of the control and 1 mg/kg extract-treated animals were 45.3 +/- 2.5 and 100.9 +/- 14.0 mmHg, respectively. The extract, cGMP and IBMX alone induced dose dependent muscle relaxation. B. superba significantly enhanced the effects of cGMP and IBMX. The results suggest that ethanol extracts of B. superba are effective in enhancing penile erection. The dried root core extract from Phrae is the most effective part with a maximal dose of 1 mg/kg. The results also suggest that B. superba may act through cAMP/cGMP pathways.

Vasomotor action of insulin on the rabbit normal cavernous smooth muscle

Investigations on the effects of insulin on the normal vasculature have produced conflicting results. This study was aimed at establishing the vasomotor actions of insulin on normal cavernous smooth muscle. Insulin produced dose-dependent (10 − 10 –10 − 5 M) relaxation of the norepinephrine-precontracted strips of cavernosum, and of Bay K8644 [methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-2(trifluoromethylphenyl)pyridine-5-carboxylate]-precontracted strips. Endothelial denudation or indomethacin (10 μM) pre-treatment significantly reduced these insulin-induced relaxations, whereas N G-nitro- l-arginine methyl ester (L-NAME, 5 mM) did not. Moreover, the pre-treatment of the cavernosum strips with a prostacyclin synthesis inhibitor [9,11-diazo-15-deoxy-prostaglandin H 2 (U-51605), 10 μM] significantly reduced insulin-induced response, whereas pretreatment with a cyclooxygenase-2 (COX-2) inhibitor (NS-398, 10 μM) did not. In addition, responses to insulin were not inhibited by K + channel blockers, i.e., tetraethylammonium (TEA, 10 mM) or 4-aminopyridine (4-AP, 10 μM). Moreover, L-type Ca 2+ currents were reduced by prostacyclin (2 μM) but not by insulin (10 μM). We conclude that insulin induces the endothelium-dependent relaxation of cavernous smooth muscles and that this relaxation response may emanate from the direct inhibition of L-type Ca 2+ channels by prostacyclin.

Experimental study of verapamil on the relaxation of isolated human corpus cavernosum tissues

To evaluate the relaxant effect of verapamil on human corpus cavernosum in vitro and to assess the drug's potential as a treatment for erectile dysfunction (ED). Preparations of the human corpus cavernosum were obtained from recently deceased young men who had had normal erectile function. The isometric tension and detailed curves were recorded when contractions induced by 10 micromol/L phenylephrine were reduced by different doses of verapamil or the vehicle control (sterile water). The tension of human corpus cavernosum preparations are described as a percentage of their top tension before adding verapamil or the vehicle. ANOVA and least significant difference tests were used for statistical analysis. Doses of 1 micromol/L, 10 micromol/L and 100 micromol/L verapamil resulted in relaxation of (35.28+/-7.96)%, (55.91+/-6.41)%, (85.68+/-4.16)% after 30 min, respectively. The vehicle control at the same time point produced relaxation of (-0.06+/-10.57)% (P<0.05). Verapamil is significantly effective in relaxing normal human corpus cavernous smooth muscle induced by phenylephrine in vitro and the relaxant effect depends on the concentration of verapamil.

Corpus cavernosum electromyography, a usable clinical diagnostic method for erectile dysfunction?

Corpus cavernosum electromyography (CC-EMG) has been intensively studied as a potential clinical tool for evaluating the function of the cavernous smooth muscle and its autonomic innervations since 1989. Both basic and clinical studies have shown promising results. However, its application as a diagnostic tool with clinical relevance was hindered by insufficient knowledge of cavernous smooth muscle electrophysiology and a series of technical and practical difficulties. Recently, major progress has been made to overcome these difficulties. Multichannel monopolar recording method has been proved to be superior to traditional one or two-channel bipolar recording. Correlation techniques have been applied as a comprehensive, objective and easy-to-use method to analyze CC-EMG recordings. Using these newly developed techniques, CC-EMG has been demonstrated to be discriminative in erectile dysfunction patients with conditions that are associated with cavernous smooth muscle degeneration and/or autonomic neuropathy from men with normal erectile function. However, before CC-EMG can be used as a robust method for erectile dysfunction-diagnostics, some basic and clinical issues are still to be solved. This review presents an overview of the latest advances in CC-EMG studies, mainly focusing on the clinical application of this method as a diagnostic tool. Furthermore, the background knowledge of cavernous electrophysiology, the problems to be overcome and future perspectives are also discussed.

Insulin Resistance and Erectile Dysfunction

Sae-Chul Kim From the Department of Urology, Chung-Ang University College of Medicine, Seoul, Korea Insulin resistance is a hallmark of metabolic syndrome, including type 2 diabetes mellitus and obesity which are characterized by endothelial dysfunction. The endothelial dysfunction leads to erectile dysfunction (ED). Thus, understanding of insulin resistance is mandatory for urologists to understand a pathophysiology of ED. There are two distinct features of insulin signal transduction pathway. One is phosphatidylinositol 3-kinase-dependent pathway which regulates glucose uptake in skeletal muscle and nitric oxide (NO) production and vasodilation in vascular endothelium. In cavernous smooth muscles, insulin also induces the endothelium-dependent relaxation, however it may emanate from the direct inhibition of L-type Ca channels by prostacyclin in addition to NO production. The other one is mitogen-activated protein (MAP)-kinase pathway which regulates growth and mitogenesis and controls secretion of endothelin-1 in vascular endothelium. Stimulation of sympathetic activity by insulin may also contribute to hemodynamic regulation. A shift in balance between vasoconstrictor and vasodilator actions of insulin may be an important factor in the vascular pathophysology of insulin resistance, leading to ED. Hyperglycemia, elevated free fatty acid levels, and proinflammatory states share mechanisms between insulin resistance and endothelial dysfunction. There is evidence to suggest that testosterone is an important regulator of insulin sensitivity in men and hypotestosteronemia may have a role in the pathogenesis of insulin-resistant states. (Korean J Urol 2006;47:917-927) 대한비뇨기과학회지 제 47권 제 9호 2006

Treatment with Hypotensive Agents Affects the Impaired Relaxation of the Penile Corpus Cavernosum in Hypertensive Rats

Treatment of erectile dysfunction (ED) in hypertensive subjects remains to be formally established. There is currently no standardized treatment for ED in hypertensive subjects. In this study, we tested our hypothesis that hypotensive drugs would improve impaired relaxation in the corpus cavernosum of spontaneously hypertensive rats (SHR). Ten-week-old SHR was treated with amlodipine, imidapril or hydralazine for 4 weeks. Although all three drugs achieved an equivalent decrease in systolic blood pressure (SBP), only amlodipine and imidapril induced an increase in relaxation in response to electrical field stimulation (EFS) of the corpus cavernosum. In the case of amlodipine, this effect was dose- and SBP-dependent. Nitric oxide (NO)-dependent relaxation was increased by amlodipine over a wide range of EFS frequencies, was increased by imidapril at low EFS frequencies, and was decreased by hydralazine. Carbon monoxide (CO)-dependent relaxation was only increased by hydralazine, and this increase occurred over a wide range of frequencies. The NOx and cGMP levels in the EFS-stimulated corpus cavernosum were increased by amlodipine. Amlodipine did not affect the thiobarbituric acid-reacting substance levels in the serum and the corpus cavernosum, but did decrease superoxide dismutase activity in the tissue. Imidapril and hydralazine inhibited the acetylcholine-induced relaxation in the corpus cavernosum. Sodium nitroprusside-induced relaxation in the tissue was increased by amlodipine. All three agents similarly inhibited the phenylephrine-induced contraction. These results suggest that impaired neurogenic relaxation in the corpus cavernosum of SHR is improved by amlodipine and imidapril through an increase in the synthesis and/or release of neuronal NO, but not CO, and presumably the inhibited detumescence of erection, which is induced by norepinephrine being released from sympathetic neuron. These findings indicate that amlodipine and imidapril may ameliorate the decreased relaxation of cavernous smooth muscle in the setting of hypertension.

Diabetes induced alteration of clitoral hemodynamics and structure in the rabbit.

We investigated the effect of diabetes on clitoral hemodynamics and structures in the rabbit. A total of 25 New Zealand White female rabbits weighing 3 to 3.5 kg. were divided into 2 groups, including 5 in the control and 20 in the experimental group. Experimental animals received intravenous injection of alloxan hydrochloride (Sigma Chemical Co., St. Louis, Missouri) (100 mg./kg.). The development of diabetes was verified by measuring body weight and blood glucose levels. After 12 weeks clitoral cavernous blood flow in ml. per minute per 100 gm. tissue was measured with a laser Doppler flowmeter. Cross sections of the clitoris were used for histochemistry and histomorphometric image analysis. After 12 weeks 5 animals were included in the diabetes group. Mean baseline flaccid and peak clitoral cavernous blood flow plus or minus standard deviation significantly decreased in the diabetic group compared with the control group (3.9 +/- 1.6 and 5.8 +/- 2.2 versus 7.2 +/- 2.5 and 12.9 +/- 5.8 ml. per minute per 100 gm. tissue, respectively, p <0.05). Histology revealed diffuse clitoral fibrosis in the diabetic group. On histomorphometry the mean proportion of clitoral cavernous smooth muscle in the diabetic group was significantly decreased compared with the control group (51.9% +/- 4.9% versus 62.3% +/- 3.1%, p < 0.05). These results show that diabetes mellitus produces significant adverse effects on the hemodynamic mechanism of clitoral engorgement and leads to diffuse clitoral cavernous fibrosis. It implies that decreased sexual arousal in diabetic women may result from structural changes in the clitoris.